Interaction of glutathione peroxidase-1 and selenium in endemic dilated cardiomyopathy.
BACKGROUND
Keshan disease (KD) is a fatal dilated cardiomyopathy with unknown etiology. We studied the gene-environment interaction in the pathogenesis of KD by assessing the association of low blood selenium and polymorphisms in glutathione peroxidase-1 (GPx-1) gene.


METHODS
The concentration of blood selenium and the activity and polymorphisms of GPx-1 in 71KD patients and 290 controls were measured. The functions of rat neonatal cardiomyocytes resulting from overexpression of 2 variants of GPx-1 were studied.


RESULTS
Blood concentration of selenium and GPx-1 activity were lower in patients than in controls. Genetic analysis revealed a single nucleotide polymorphism (Pro198Leu) in GPx-1 gene associated with selenium deficiency as well as impaired GPx-1 activity. Gene-environment interaction analysis revealed a synergistic-multiplicative interaction between polymorphism of GPx-1 and selenium deficiency. Overexpression of the GPx-1 leucine-containing allele in cultured cardiomyocytes caused a 30% reduction in selenium-induced GPx-1 activity and increased serum starvation induced apoptosis as compared with that of the wild-type variant 198Pro.


CONCLUSIONS
Selenium deficiency in carriers with the GPx-1 leucine-containing allele is associated with low GPx-1 enzyme activity, which may, in turn, increase the incidence of KD. Results from this unique disease may have broad implications for a gene-environment reaction in the etiology of other diseases.
Lei
Cong
C
Department of Cardiology, The Second Affiliated Hospital, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710004, P.R. China.
Niu
Xiaolin
X
Wei
Jin
J
Zhu
Jianhong
J
Zhu
Yi
Y
D000368:Aged; D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004796:Clinical Enzyme Tests; D005838:Genotype; D005979:Glutathione Peroxidase / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic; D051381:Rats; D012643:Selenium / Q000097:blood* / Q000172:deficiency*; D000094765:Glutathione Peroxidase GPX1
D005979:Glutathione Peroxidase; D007930:Leucine; D012643:Selenium; D000094765:Glutathione Peroxidase GPX1